Dr. Nanette K. Wenger from the Emory University School of Medicine moderated the topic "HDL and Triglycerides in the Year 2011," with Drs. Christie Ballantyne from the Baylor College of Medicine and Michael Davidson from the University of Chicago School of Medicine participating.

The discussion focused primarily on:

(1) speculation as to the recommendations that might be made in the NCEP ATP IV Guidelines, particularly about non-HDL cholesterol

(2) gender specific recommendations with emphasis on the AHA guidelines,

DR. WENGER: Let me welcome you all to the Expert Medical Roundtable on high-density lipoprotein (HDL) cholesterol and triglycerides in the year 2011. I am Dr. Nanette Wenger, Professor of Medicine in the Division of Cardiology at the Emory University School of Medicine. With me are Dr. Michael Davidson, who is Clinical Professor of Medicine and the Director of Preventive Cardiology at the University of Chicago School of Medicine, and Dr. Christie Ballantyne, Chief of the Sections of Cardiology and Cardiovascular Research at the Baylor College of Medicine.

The last official published guidelines regarding cholesterol management date back a decade, to the 2001 National Cholesterol Education Program Adult Treatment Panel III recommendations for lipid management,1 with a small modification a few years later just lowering the LDL goal optionally for patients at high risk. Excitingly, during the past decade, we have experienced remarkable levels of LDL control with statin therapy and many reports of consequent declines in coronary events.

Yet coronary events still occur, even in the presence of optimal levels of low-density or LDL lipoprotein cholesterol. Many have termed this occurrence “residual risk,” which is not a bad term. Many patients with residual risk have type II diabetes, metabolic syndrome, or obesity, so that we considered it was now time to readdress the implications of low levels of HDL cholesterol, high levels of triglyceride and potential therapies for these lipid abnormalities.

Dr. Davidson, let me start with you. As you know, the NCEP ATP III focused only on LDL, and, when the triglyceride levels were greater than 200, on non-HDL cholesterol. Look into your crystal ball and tell me what you might anticipate the changes will be when NCEP ATP IV is published, hopefully later this year.

DR. DAVIDSON: I think it’s going to be hard to say exactly what the ATP IV2 is going to recommend, but I believe one important change is going to be the emphasis on non-HDL cholesterol (LDL and triglycerides) being potentially a co-primary goal of therapy with LDL cholesterol. One of the big disappointments about non-HDL cholesterol in the ATP III guidelines was that doctors don’t look at it and it’s not on the lab sheet. So consequently, if you look at surveys of treatment, you’ll find that although LDL cholesterol goals are much improved over what they were a decade ago, the treatment to non-HDL targets is still very much suboptimal. So I think one key modification of ATP IV will be to focus on non-HDL cholesterol as a treatment target equal to that of LDL cholesterol, so you don’t have a secondary target type of priority for non-HDL cholesterol, but move it to a co-primary with LDL cholesterol.

The reason for this is the fact that, in all the most recent trials, it is more likely that you’re going to find that non-HDL cholesterol predicts better than LDL cholesterol when it comes to recurrent cardiovascular events, especially on statin treatment. So therefore there is an evidence-based rationale to shift more priority to non-HDL cholesterol. One potential is to do away with LDL cholesterol and to focus only on non-HDL cholesterol. I don’t think the ATP IV panel will go that far, but certainly, the elevation of non-HDL cholesterol to a co-primary target will be a likely part of the new guidelines.

DR. WENGER: For practicality, both for the patient and for the clinician, non-HDL-C is a non-fasting measurement, which makes it so much more attractive in terms of actual use. Any other changes that you might anticipate?

DR. DAVIDSON: I think another benefit of utilizing non-HDL cholesterol as a target is that it can be accurately measured non-fasting. I should point out, the main reason why non-HDL cholesterol is becoming more predictive than LDL cholesterol is because, in the last ten years, we’ve seen this tremendous change with the type of patient presenting for an acute coronary syndrome (ACS). Patients with ACS are now far more likely to have metabolic syndrome, diabetes and high triglycerides with low HDL. They’re also the patients who are more likely to have events on a statin. Therefore, non-HDL cholesterol, which incorporates both LDL and VLDL (triglycerides) into a single number as a target, is a better measurement of risk in the patients who will more likely present with an acute coronary event.

With regard to other changes, I think ATP IV will include lifetime risk instead of just ten-year risk as a tool to initiate therapy earlier in some high-risk individuals. Based on clinical trial evidence, the treatment of people with diabetes over age 40 or those with established coronary disease, ATP IV will likely recommend the initiation of statin therapy regardless of the baseline LDL cholesterol. ATP III1 did not recommend initiation of therapy regardless of the baseline LDL cholesterol.

The JUPITER3,4 study also supports that in high risk patients, defined as men and women, over 50 and 60, respectively, with an additional risk factor of a high sensitivity CRP (hs-CRP) over 2 mm/L, giving a statin reduces events, regardless of the baseline LDL cholesterol. Therefore another potential important change may be to measure hs-CRP in patients with an LDL cholesterol <130mg/dl, and initiate statin therapy regardless of their baseline LDL cholesterol. The clinical trial evidence would support at least a 35%–50% LDL cholesterol reduction to achieve a significant clinical benefit in this population.

DR. WENGER: Dr. Ballantyne, let me ask you the next question. The epidemiologic data are rather powerful, showing that the risk is greater for women than for men with both high triglyceride and low HDL levels. Based on these epidemiologic data, and acknowledging that we don’t have clinical trial data, do you think there should be a gender-specific recommendation?

DR. BALLANTYNE: I agree with the recent AHA guidelines that looked at prevention of cardiovascular disease in women5 where an HDL cut point for HDL cholesterol of 50 mg/dL defined risk. Now that’s different than ATP III, which mentioned less than 40 mg/dl. ATP III made the argument that for men and women, the absolute risk was similar with low HDL levels.

Even in ATP III, though, when they discussed the metabolic syndrome, they moved to a higher HDL of less than 50 mg/dl. So let’s look at some of the reasons for the 50 mg/dl level. I think this is the key issue for women—we need to look at not only the absolute risk over ten years, but also the lifetime risk, which really is similar to what we used to call the relative risk. In a younger person with a high relative risk, over a long period of time, they have a high lifetime risk. When you see an HDL of less than 50 mg/dl, that is low for women. It’s very often associated with concomitant comorbidities, hypertension, obesity, elevated triglycerides, and insulin glucose resistance. These are individuals where lifestyle modification can have a major impact, so I’m highly supportive of that.

One of our goals in prevention is to try to motivate people to modify their lifestyle and comply with their medications. In particular, when we’re talking to women and you tell a woman, “Well, you’re at low risk.” In the Framingham risk profile it’s less than 10% for CHD, let’s say it’s 8% over ten years.6 That ignores the risk for stroke. It also ignores the risk for revascularization and for angina. Most of our patients would consider these to be pretty serious problems. I certainly would consider it a serious problem for myself. I really don’t understand why we underestimate the total cardiovascular risk in patients when we’re trying to motivate them. So I was very pleased that your guidelines noted that we should be looking at the cardiovascular risk. I think we should include both hard and soft cardiovascular risk, because there really is a big difference. The risk for nonfatal MI and death from MI might be 8%, but if you throw in everything else for women, the number is much higher. Stroke is actually quite common in women, as compared to CHD events and revascularization is much more common. You might tell someone that they’re low risk when they can be over 20%, if you look at total events.

Another important thing I liked in those guidelines was the mention of triglycerides. This is a little bit tricky, in terms of whether they are even a risk factor, but certainly they’re a good risk marker. When you see a triglyceride of over 150 in a woman, we should be thinking about the same things I mentioned: metabolic syndrome, hypertension, insulin resistance and diabetes.

DR. WENGER: I am delighted that you were as pleased with the new women’s prevention guidelines as we, the Writing Committee, were. A new aspect of the 2011 update to the women’s prevention guidelines is the emphasis on cardiovascular disease and not solely on coronary disease, of course, continuing the emphasis of the prior guideline on lifetime risk as truly important. But again, in the guideline we emphasized lifestyle, lifestyle, lifestyle first, for all women, and then other interventions.

Dr. Davidson, let’s examine diabetic compared to non-diabetic patients. What type of clinical trial data do we have for the role of therapy of high triglycerides and low HDL levels and the difference in diabetic and non-diabetic populations?

DR. DAVIDSON: Unfortunately, we don’t have a lot of evidence to focus on in the studies that compare one to the other. We do know that, for example, in the Heart Protection Study,7 the diabetic patient population, which is at high risk, benefit significantly with statins, regardless of the baseline LDL cholesterol. We also know that low HDL and high triglycerides confer additional risk for subsequent events for those with or without diabetes, but the presence of diabetes elevates the risk significantly.

So if you look at rating risk, the metabolic syndrome patient is at increased risk, compared to those without the metabolic syndrome. Then once you go to diabetes, their risk appears to be increased. In patients with diabetes and the metabolic syndrome, which is most of the people with diabetes, their risk is even higher. Then if you add in coronary disease, the risk is even greater. Patients with both coronary disease and the metabolic syndrome or diabetes have the greatest risk. Therefore patients with metabolic syndrome or diabetes deserve special attention when it comes to and treating assessing risk factors.

As a part of the ADA/ACC Consensus Conference Statement of Lipoprotein Management in 2008,8 we had a lot of debate about the lipid targets for patients without CVD, with diabetes or the metabolic syndrome. We came up with a recommendation for an LDL cholesterol target less than 70 mg/dl, and non-HDL cholesterol target less than 100 mg/dl if the patient has evidence of the metabolic syndrome/diabetes and an additional risk factor. There wasn’t significant trial evidence to support this recommendation, but we believed there was considerable evidence that these patients are destined to have an event in the future. Their lifetime risk is high, so why wait for the event to start treating them more aggressively? Once they have an event, their prognosis remains much less optimistic, and the long-term prognosis is poor.

What we were hoping to do with a prevention strategy like this is to target the highest risk patient, get their LDL cholesterol down to at least 70 mg/dl, and the non-HDL cholesterol below 100 mg/dl. Consider ApoB measurements once they have achieved those LDL and non-HDL targets to make sure that they are truly at the ApoB target, which may not be concordant with their LDL cholesterol and non-HDL cholesterol. You’ll frequently see discordance between ApoB and non-HDL cholesterol and LDLcholesterol in those high-triglyceride, low-HDL patients. Hopefully we can prevent an event.

DR. WENGER: Of course, this emphasizes the importance of the detection of diabetes, because there is so much unrecognized diabetes in the population at large. Once you identify a patient, man or woman, as diabetic, there are totally different intensity goals for so many of their risk factor managements.

Let’s move on to some of the clinical trials that have been quoted and misquoted, interpreted and misinterpreted. Dr. Ballantyne, I will ask you first to talk about ACCORD. Let’s just confine this discussion to the lipid component of ACCORD9,10 and tell me what you think ACCORD has taught us?

DR. BALLANTYNE: As you know, ACCORD was an ambitious trial, which followed diabetic patients and looked at important questions in regard to glucose control, blood pressure control and lipid therapy. Maybe one thing that we learned is, if you try to look at too many things at one time, you don’t always get a very clear answer. Unfortunately, when you design these trials, they’re hard to recruit. So there was some compromise here, in that they enrolled patients with diabetes who were on statins. The study tested whether the combination of fenofibrate plus simvastatin conferred more benefit than statin alone. To make recruitment easier, patients were admitted to the study who didn’t have the typical lipid criteria that we use when we use a fibrate. Typically, fibrates, at least for most of us, are reserved for patients who have a high triglyceride and a low HDL cholesterol or a very high triglyceride. Those were not the criteria. Overall there was no benefit from the combinations used in this study.10

There was a subgroup that had elevated triglycerides and low HDLs. This group had an event reduction following aggressive lipid-lowering therapy. Now the P for the interaction for treatment effect for this subgroup compared to the overall study was 0.057,10 so that was not significant, but it’s consistent with data from numerous other trials. It appears the benefits of fibrates are greater in patients who have a combination of low levels of HDL and high triglycerides with little or no benefit in patients with normal triglycerides and HDL levels. Another consideration is the presence of very high triglycerides but as you know, this is a less common condition and they weren’t entered into this study.

“So I think one key modification of ATP IV will be to focus on non-HDL cholesterol as a treatment target equal to that of LDL cholesterol.”~ Michael Davidson, MD

“But again, in the [AHA] guideline we emphasized lifestyle, lifestyle, lifestyle first, for all women, and then other interventions.”~ Nanette Wenger, MD

“Now in terms of HDL raising, lifestyle modifications usually are fairly modest, but the more exercise you do and the more weight you lose, the greater the benefits.”~ Christie Ballantyne, MD

“Given the variety of rather powerful statin drugs that enable reducing LDL cholesterol levels to extremely low values, is there any level of LDL below which any other interventions may not provide significant benefit?”~ Nanette Wenger, MD